Management of pain and inflammation is the most critical aspect of dental practice. Inadequate pain control affects patients in many ways beyond the treatment and its outcome. Inflammation of tissues inside the tooth (pulpitis) and surrounding the tooth (apical periodontitis) induced by injury and/or infection is a major cause of tooth pain due to thermal hyperalgesia and mechanical allodynia. Hyperalgesia manifests clinically as increased and prolonged painful response to thermal stimuli, while mechanical pain from allodynia appears as painful responses to biting, percussion, palpation, and other non-noxious/non-painful stimuli. In response to the inflammation, sensory neurons secrete neuropeptides especially Calcitonin Gene Related Peptide (CGRP) from their peripheral nerve endings, causing vasodilatation and plasma extravasation in tissues inside and surrounding the tooth. These neuropeptides exacerbate inflammatory reactions and lead to an increased receptive field of peripheral nerve endings, altering nerve resting potentials, increasing neural excitability, and up-regulating expression of tetrotoxin-resistant (TTX-R) sodium (Na+) channels, Nav1.8 and Nav1.9 in the dental pulp4, 7, 14, 15, 20. Conversely, we observed that incubation of the CGRP receptor antagonist CGRP8-37 decreased Na+ current density in DRG neurons (see Preliminary Studies). These findings suggest that excessive CGRP augments Na+ channels, which may underlie the failure of local anesthetic agents to attain effective pulpal anesthesia in the inflamed tooth prior to surgical intervention and the extensive use of nonsteriodal anti-inflammatory drugs (NSAIDs), or even opiates post-surgery. Currently, there are no effective and safe analgesics with anti-neuroinflammation properties available for these conditions. The mainstay treatment is to surgically remove infected and inflamed neural tissues inside the tooth by root canal treatment. This method is effective in managing pain by removing the altered neural tissues inside the tooth. However, a new therapeutic is of great need to block the pain completely before performing the root canal treatment procedure, and to prevent the transition from acute pain to prolonged or even chronic pain after the surgery. Further, changes in neural tissues outside the tooth due to peripheral and central neural sensitization can remain even after the root canal operation and contribute to the development of persistent pain. Postoperative pain was estimated to affect 10-46% of patients receiving root canal treatment due to painful pulpitis and apical periodontitis25-30. Here, we propose to use our novel AFA-P3, a 12-amino acid antagonist selectively against the CGRP receptor, for local treatment of dental inflammatory pain. Our preliminary data showed that P3 displayed higher binding affinity than the conventional 31-amino acid antagonist CGRP8-37, inhibiting CGRP receptors and downstream signaling more effectively. Further, P3 mitigated thermal hyperalgesia in teeth with pulpitis and restored local anesthetic efficacy of 2% lidocaine to attain effective pulpal anesthesia of the inflamed teeth. We propose this SBIR Phase I study with the following Specific Aims. Aim1: To determine P3 efficacy in alleviating neuroinflammatory pain following pulpitis and apical periodontitis induction in mice. Aim2: To investigate how P3 modulates neuroinflammation, and TTX-R Na+ channel expression and activity. Success in this Phase I project will lead to a Phase II to further develop a novel therapeutic to produce dental analgesia via anti-neuroinflammation, and to increase effectiveness of dental local anesthetics for the management of painful pulpitis and/or apical periodontitis.